The present invention relates to a class of diaryl-enynes, to pharmaceutical compositions containing them and to methods of treating neurological and neuropsychiatric disorders using such compounds.
Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic terminal and surrounding glial cells (Kanner and Schuldiner. CRC Critical Reviews in Biochemistry, 22, 1987:1032). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighbouring synapses, transporters maintain the fidelity of synaptic transmission. Lastly, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
Neurotransmitter transport is dependent upon extracellular sodium and the voltage difference across the membrane; under conditions of intense neuronal firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Attwell et al., Neuron, 11, 1993:401-407). Pharmacologic modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are thus referred to as xe2x80x9cstrychnine-sensitivexe2x80x9d. Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
Glycine also functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system (Johnson and Ascher, Nature, 325, 1987:529-531; Fletcher et al., Glycine Transmission, Otterson and Storm-Mathisen, eds., 1990:193-219). Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that it will fire an action potential.
NMDA receptors in the hippocampal region of the brain play an important role in a model of synaptic plasticity known as long-term potentiation (LTP), which is integral in certain types of learning and memory (Hebb, D. O (1949) The Organization of Behavior; Wiley, NY; Bliss and Collingridge (1993) Nature 361: 31-39; Morris et al. (1986) Nature 319: 774-776). Enhanced expression of selected NMDA receptor sub-units in transgenic mice results in increased NMDA-receptor-mediated currents, enhanced LTP, and better performance in some tests of learning and memory (Tang et al. (1999) Nature 401: 63).
Conversely, decreased expression of selected NMDA receptor sub-units in transgenic mice produces behaviors similar to pharmacologically-induced animal models of schizophrenia, including increased locomotion, increased stereotypy, and deficits in social/sexual interactions (Mohn et al. (1999) Cell 98:427-436). These aberrant behaviors can be ameliorated using the antipsychotics haloperidol and clozapine.
NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Molecular cloning has revealed the existence in mammalian brains two classes of glycine transporters, termed GlyT-1 and GlyT-2. GlyT-1 is found throughout the brain and spinal cord, and it has been suggested that its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992:927-935). Molecular cloning has further revealed the existence of three variants of GlyT-1, termed GlyT-1a, GlyT-1b and GlyT-1c. Two of these variants (1a and 1b) are found in rodents, each of which displays a unique distribution in the brain and peripheral tissues (Borowsky et al., Neuron, 10, 1993:851-863; Adams et al., J. Neuroscience, 15, 1995:2524-2532). The third variant, 1c, has only been detected in human tissues (Kim, et al., Molecular Pharmacology, 45, 1994:608-617). These variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT-2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993:22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995:1026-1033). Another distinguishing feature of glycine transport mediated by GlyT-2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT-1. These data are consistent with the view that, by regulating the synaptic levels of glycine, GlyT-1 and GlyT-2 selectively influence the activity of NMDA receptors and stryclnine-sensitive glycine receptors, respectively.
Compounds which inhibit or activate glycine transporters would thus be expected to alter receptor function and, thus, provide therapeutic benefits in a variety of disease states.
For example, compounds which inhibit GlyT-1 mediated glycine transport will increase glycine concentrations at NMDA receptors, which receptors are located in the forebrain, among other locations. This concentration increase elevates the activity of NMDA receptors, thereby alleviating schizophrenia and enhancing cognitive function. Alternatively, compounds that interact directly with the glycine receptor component of the NMDA receptor can have the same or similar effects as increasing or decreasing the availability of extracellular glycine caused by inhibiting or enhancing GlyT-1 activity, respectively. See, for example, Pitkxc3xa4nen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569 (1996).
The present invention provides compounds that affect glycine transport. The invention also provides compositions useful to treat medical conditions for which a glycine transport modulator, and particularly glycine uptake inhibitors, are indicated.
According to one aspect of the invention, there are provided compounds of Formula I: 
wherein:
Ar1 and Ar2 are independently selected aryl groups, optionally substituted with up to five substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio, thioaryl-alky, aralkylthioalkyl, halo, NO2, CF3, CN, OH, alkylenedioxy, SO2NRRxe2x80x2, NRRxe2x80x2, CO2R (where R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl) and a second aryl group, which may be substituted as above;
R1 is selected from the group consisting of H and alkyl;
R2 is selected from the group consisting of H, alkyl and benzyl;
R3 is selected from the group consisting of CO2R, CONRRxe2x80x2, CONH(OH), COSR, SO2NRRxe2x80x2, PO(OR)(ORxe2x80x2) and tetrazolyl, wherein R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl;
and a salt, solvate or hydrate thereof.
It has been found that compounds of Formula I inhibit glycine transport (or reuptake) via the GlyT-1 transporter, or are precursors (for example, pro-drugs) of such compounds and, thus, are useful in the treatment of schizophrenia, as well as other CNS-related disorders such as cognitive dysfunction, dementia (including that related to Alzheimer""s disease), attention deficit disorder and depression.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of Formula I in an amount effective to inhibit glycine transport, and a pharmaceutically acceptable carrier.
In another aspect of the invention there are provided compositions containing the present compounds in amounts for pharmaceutical use to treat medical conditions for which a glycine transport inhibitor is indicated. Preferred are those compositions containing compounds useful in the treatment of medical conditions for which GlyT-1-mediated inhibition of glycine transport is needed, such as the treatment of schizophrenia or cognitive dysfunction.
The term aryl as used herein means a monocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, and the like, or a benzo-fused aromatic group such as naphthyl, indanyl, quinolinyl, fluorenyl and the like.
The term alkyl as used herein means straight- and branched-chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl and the like.
The term cycloalkyl as used herein means a carbocyclic ring containing from three to eight carbon atoms and includes cyclopropyl, cyclohexyl and the like. Similarly, the term xe2x80x9ccycloalkyloxyxe2x80x9d refers to such a carbocycle that is coupled through an oxygen to another group, and includes cyclohexyloxy and the like.
The term heterocycloalkyl as used herein means a three- to eight-membered ring containing up to two heteroatoms selected from the group consisting of N, S and O, and includes piperidinyl, piperazinyl, thiopyranyl and the like. Such rings coupled to another group through an oxygen, such as piperidinyloxy and the like, are referred to as heterocycloalkyloxy groups.
The terms aralkyl, aryloxyalkyl, aralkyloxy and aryloxyalkoxy as used herein refer to an alkyl or alkoxy radical substituted with an aryl or aryloxy group and includes benzyl, phenethyl, benzyloxy, 2-phenoxyethyl and the like. Similarly, the terms cycloalkyl-substituted alkyl, cycloalkyl-substituted alkoxy, heterocycloalkyl-substituted alkyl and heterocycloalkyl-substituted alkoxy mean groups such as 2-cyclohexyl-ethyl and the like. Further, substituents in which an alkyl or alkoxy group is substituted by another group through a bridging oxygen, are groups referred to herein as cycloalkyloxy-substituted alkyl, cycloalkyloxy-substituted alkoxy, heterocycloalkyloxy-substituted alkyl and heterocycloalkyloxy-substituted alkoxy.
The terms alkylene (e.g., xe2x80x94CH2xe2x80x94CH2xe2x80x94), alkenylene (e.g., xe2x80x94CHxe2x95x90CHxe2x80x94) and alkynylene (e.g., xe2x80x94CHxe2x89xa1CHxe2x80x94) as used herein means straight- and branched-chain bivalent radicals containing from one to six carbon atoms, such as methylene, ethylene, vinylene, propenylene and ethynylene.
The terms alkylene (e.g., xe2x80x94CH2xe2x80x94CH2xe2x80x94), alkenylene (e.g., xe2x80x94CHxe2x95x90CHxe2x80x94) and alkynylene (e.g., xe2x80x94CHxe2x89xa1CHxe2x80x94) as used herein means straight- and branched-chain bivalent radicals containing from one to six carbon atoms, such as methylene, ethylene, vinylene, propenylene and ethynylene.
The term alkoxy as used herein means straight- and branched-chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy and the like.
The term thioalkyl as used herein means straight- and branched-chain alkyl radicals containing from one to six carbon atoms and includes thiomethyl (CH3xe2x80x94Sxe2x80x94), thiopropyl and the like.
The term thioaryl refers to an aryl group that is bridged to another group through a sulfur. Similarly, a thioarylalkyl group is a thioaryl group bridged to another group through an alkylene group. Also, an aralkythio group is an aralkyl group, such as benzyl, which is bridged to another group through a sulfur atom. Further, an arylalkylthioalkyl group is an arylalkyl group that is bridged to another group through a thioalkyl group.
The term alkanoyl as used herein means straight- and branched-chain radicals containing from one to six carbon atoms and includes acetyl, propionyl and the like.
The term halo as used herein means halogen and includes fluoro, chloro, bromo and the like. The term haloalkyl refers to an alkyl group substituted by one or more independently selected halo atoms, such as xe2x80x94CF3. Similarly, the term haloalkoxy refers to an alkoxy group substituted by one or more independently selected halo atoms, such as xe2x80x94OCF3.
The term alkylenedioxy refers to a group of the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94, in which the terminal oxygen typically are fused to atoms on an aryl group to form a bicyclic ring system, and includes methylenedioxy, ethylenedioxy and the like.
The term hetero atom as used herein means atoms other carbon and includes N, S and O.
The geometry about the double bond of the compounds of Formula I is as drawn. That is, group Ar2 and the carbon atom to which group R1 is attached are cis to each other.
Compounds of Formula I include those in which Ar1 and Ar2 are, independently, optionally-substituted aryl groups.
Substitution sites on rings Ar1 and Ar2 will be limited in practice to the carbon atoms on the ring not bound to the core of the molecule. For example, a benzene ring can be substituted with up to 5 substituents; pyridine and pyran can accommodate up to 4 substituents pyrole furan and thiophene can accommodate up to 3 substituents; imidazole 2 substituents and triazole can accommodate only one substituent.
In embodiments of the invention Ar1 is an optionally monocyclic aromatic group such as benzene, pyridine, pyran, thiophene, furan, pyrole, imidazole and triazole. Ar1 suitably accomodates 1, 2 or 3 substituents on the aromatic ring and these can be chosen from such groups as alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio, thioaryl-alky, halo, NO2, CF3, CN, OH, methylenedioxy, ethylenedioxy, SO2NRRxe2x80x2, NRRxe2x80x2, CO2R (where R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl) or an aryl group optionally substituted as stated above.
In suitable embodiments of the invention, Ar1 is selected from benzene, pyridine, pyran, thiophene, furan and pyrole, optionally substituted with 1, 2 or 3 substituents selected from halo, NO2, CF3, CN, OH, alkyl, alkoxy, aryl, aralkyl, and Rxe2x80x3(X)n. where n is 0 or 1; X is CH2 or a heteroatom; and Rxe2x80x3 is H, alkyl or aryl substituted optionally with up to three substituents selected from alkyl, halo, NO2, CF3, CN, OH, SO2NRRxe2x80x2, NRRxe2x80x2, and CO2R (where R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl).
In particular embodiments, Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, NO2, CF3, CN, OH, and Rxe2x80x3(X)n. where n is 0 or 1; X is CH2 O, S, or NR; and Rxe2x80x3 is H, alkyl or aryl substituted optionally with up to three substituents selected independently from alkyl. halo, NO2, CF3, CN, OH, SO2NRRxe2x80x2, NRRxe2x80x2, CO2R (where R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl).
In more particular embodiments, Ar1 is phenyl optionally substituted with 1 or 2 substituents selected from alkyl, thioalkyl, alkoxy, halo, haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted aralkyl.
In specific embodiments, Ar1 is mono-substituted phenyl where the substituent is located at the 4 position and is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, 3-furyl, and 3-thienyl.
In other embodiments, Ar1 is an optionally substituted benzofused aromatic group such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl and the like, where the substituents can be selected from halo, NO2, CF3, CN, OH, alkyl, alkoxy, aryl, aralkyl, and Rxe2x80x3(X)n. where n is 0 or 1; X is CH2 or a heteroatom; and Rxe2x80x3 is H, alkyl or aryl substituted optionally with up to three substituents selected from alkyl, halo, NO2, CF3, CN, OH, SO2NRRxe2x80x2, NRRxe2x80x2, CO2R (where R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl).
In particular embodiments, Art can be naphthyl, quinolinyl, indanyl, or alkylenedioxyphenyl, optionally substituted with 1 or 2 substituents selected from alkyl, alkoxy, thioalkyl and aryl.
In a specific embodiment, Ar1 is selected from unsubstituted naphthalene and methylenedioxyphenyl.
In other embodiments of the invention, Ar2 is an optionally substituted aryl, where aryl, is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine and the like, or is a benzofused aromatic ring system such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl and the like. Either 1, 2, or 3 substituents may be present, and these may be independently selected from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.
In a particular embodiment, A is a monocyclic aromatic ring bearing up to three substituents selected independently from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy. In more particular embodiments, A is selected from mono or di-substituted phenyl, where the substituents are selected from halo, haloalkyl, alkyl, haloalkoxy, and alkoxy.
In specific embodiments, Ar2 is a phenyl group that is either unsubstituted or has one substituent selected from halo and alkoxy.
In more specific embodiments, Ar2 is selected from unsubstituted or mono substituted phenyl, where the substituent is selected from chloro and flouro.
In other embodiments of the invention, R3 is selected from the group consisting of xe2x80x94CO2R, xe2x80x94CONRRxe2x80x2, xe2x80x94CONH(OH), xe2x80x94COSR, xe2x80x94SO2NRRxe2x80x2, xe2x80x94PO(OR)(ORxe2x80x2) and tetrazolyl, wherein R and Rxe2x80x2 are independently selected from the group consisting of H and alkyl.
In particular embodiments, R3 is COOR. In preferred embodiments of the invention, R3 is COOH.
The compounds of Formula I include those in which R1 is selected from the group consisting of H and alkyl. Preferably, R1 is H.
The compounds of Formula I include those in which R2 is selected from the group consisting of H, alkyl and benzyl. Suitably, R2 alkyl; more preferably, R2 is methyl.
In preferred embodiments, compounds of Formula I are those in which R1 is H, R2 is methyl, R3 is COOH. In this context, Ar1 and Ar2 are desirably substituted or unsubstituted phenyl. Preferably, Ar1 is either phenyl or 4-(substituted)-phenyl. When substituted, Ar1 is desirably a 4-(alkyl)-phenyl group, particularly where the alkyl group is a straight-chain alkyl group, including 4-isopropyl-phenyl, 4-ethyl-phenyl, and 4-n-propyl-phenyl. Either in combination therewith or independently thereof, Ar2 is preferably is chloro or fluoro substituted phenyl.
In another preferred embodiment, R1 is H, R2 is methyl, R3 is COOH, Ar2 is unsubstituted phenyl and Ar1 is 4-alkyl substituted phenyl where alkyl is C1-4 straight chain.
In another preferred embodiment R1 is H, R2 is methyl, R3 is COOH, Ar2 is 2-chlorophenyl and Ar1 is 4-alkyl phenyl where the alkyl substituent is selected from ethyl and propyl.
In another preferred embodiment of the invention R1 is H, R2 is methyl, R3 is COOH, Ar1 is naphthyl, especially 2-naphthyl, and Ar2 is phenyl.
In yet another preferred embodiment of the invention R1 is H, R2 is methyl, R3 is COOH, Ar1 is 3,4-methylenedioxyphenyl and Ar2 is 3-fluoro-phenyl.
In still another preferred embodiment of the invention R1 is H, R2 is methyl, R3 is COOH, Ar2 is phenyl and Ar1 is an optionally substituted aryl substituted phenyl.
In a more preferred embodiment of the invention R1 is H, R2 is methyl, R3 is COOH, Ar2 is phenyl and Ar1 is phenyl substituted by a 5-membered heteroaryl that is optionally substituted.
In a most preferred embodiment of the invention R1 is H, R2 is methyl, R3 is COOH, Ar2 is phenyl and Ar1 is 4-(3-furyl)phenyl.
Specific compounds of Formula I include:
N-(5-(4-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(2-Fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(2,4-Difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(3-Phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine,
N-(5-(3,5-Bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(3,5-Diphenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-diphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-npropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-nbutylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-npentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-methyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(3-Phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(3-Phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl)-sarcosine
N-(3-Phenyl-5-(4-tbutylphenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-(3-furyl)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-(3-thiophene)-phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-t-Butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-t-Butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-t-Butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Isopropylphenyl)-3-(4-methoxypheny)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(3,4-Methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
N-(5-(4-Propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine
Compounds of Formula I can be considered to be amino acids or derivatives thereof. Compounds which contain, instead of a carboxylate group, a xe2x80x9ccarboxylate equivalentxe2x80x9d group, such as hydroxamic acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, amides or tetrazoles, are also considered embodiments of the present invention.
In another embodiment of the invention, the compound of Formula I is provided in labeled form, such as radiolabeled form (e.g. labeled by incorporation within its structure 3H or 14C or by conjugation to 125I). In a preferred aspect of the invention, such compounds, which bind preferentially to GlyT-1, can be used to identify GlyT-1 receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabeled compound of the invention. GlyT-1 receptor ligands are thus revealed as those that significantly occupy the GlyT-1 site and prevent binding of the radiolabeled compound of the present invention. Alternatively, GlyT-1 receptor ligand candidates may be identified by first incubating a radiolabeled form of a compound of the invention then incubating the resulting preparation in the presence of the candidate ligand. A more potent GlyT-1 receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. Base salts are preferred and sodium and potassium salts are especially preferred.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
The compounds of the present invention can be prepared by processes analogous to those established in the art. For example, compounds of Formula I are readily prepared by the method shown in Scheme 1, below. Intermediate C was prepared according to the method of Trost (Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruther, G. J. Am. Chem. Soc. 1997, 119, 698-708 ; Trost, B. M.; Hachiya, I.; McIntosh, M. C. Tetrahedron Lett. 1998, 39, 6445-6448) by coupling an arylpropiolic ester such as A with trimethylsilylacetylene B in the presence of palladium acetate and tris(2,6-dimethoxyphenyl)phosphine. Reduction of the ester to the alcohol, and treatment with N-Bromosuccinimide gave bromide D. Treatment of D with a sarcosine ester (such as tbutyl sarcosine) in the presence of base gave the intermediate sarcosine derivative E. Removal of the trimethylsilyl group (for example, by treatment with potassium carbonate in methanol), followed by introduction of the second aryl group by a Sonogashira coupling (Sonogashira, K.; Yohda, Y. and Hagihara, N.; Tetrahedron Lett., 1975, 4467), gave the diaryl species G which, upon deprotection with, for example, formic acid, gave the final product H.
This route is an attractive one for the parallel synthesis of a series of related compounds in which group Ar2 is constant, but group Ar1 represents a number of different aryl groups. Common intermediate F can be prepared in bulk, and simply treated with the appropriate aryliodide under Sonogashira conditions to yield the desired products. 
Alternatively, such compounds may also be prepared according to the route shown in Scheme 2, below. This route complements that shown above, in that it allows the parallel synthesis of a series of related compounds in which group Ar1 is constant, but group Ar2 represents a number of different aryl groups. In this case, common intermediate L can be prepared in bulk, and simply treated with the appropriate arylpropiolic ester O (readily accessible from aryliodide M by treatment with propiolic ester N in the presence of Cul and Pd(PPh3)4), under the conditions outlined above, to yield, after deprotection, products H. 
To prepare compounds in which Ar1 is Aryl-substituted phenyl (Ar3-phenyl), the following synthesis (Scheme 3) is useful. Intermediate F can be prepared according to Scheme 1, then coupled to bromoiodobenzene via Sonogashira coupling to yield species S. The arylbromide of species S can then be reacted with a boronic acid (Ar3-boronic acid) under Suzuki coupling conditions to give intermediate Gxe2x80x2. (Gxe2x80x2 is equivalent to G. Scheme 1, Where Ar1 is Ar3-phenyl). Gxe2x80x2 can then be deprotected as in Scheme 1 to give Hxe2x80x2. 
Compounds which inhibit GlyT-1 mediated glycine transport will increase glycine concentrations at NMDA receptors, which receptors are located in the forebrain, among other locations. This concentration increase elevates the activity of NMDA receptors, thereby alleviating schizophrenia and enhancing cognitive function. Alternatively, compounds that interact directly with the glycine receptor component of the NMDA receptor can have the same or similar effects as increasing or decreasing the availability of extracellular glycine caused by inhibiting or enhancing GlyT-1 activity, respectively. See, for example, Pitkxc3xa4nen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569 (1996).
The compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery. The compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice. For the oral mode of administration, the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. If desired, certain sweetening and/or flavoring agents are added. For parenteral administration, sterile solutions of the compounds of the invention are usually prepared, and the pHs of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers. For pulmonary administration, diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.
Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. See, Remington""s Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, Pa., 1980, pp. 1530-1533 for further discussion of suppository dosage forms. Analogous gels or creams can be used for vaginal, urethral and rectal administrations.
Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.
Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example. Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill.
The physician or other health care professional can select the appropriate dose and treatment regimen based on the subject""s weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 xcexcg/cc and about 1000 xcexcg/cc, preferably between about 0.1 xcexcg/cc and about 100 xcexcg/cc. For parenteral administration, an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered. For oral administrations, an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg). For administrations in suppository form, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
For use in assaying for activity in inhibiting glycine transport, eukaryokic cells, preferably QT-6 cells derived from quail fibroblasts, have been transfected to express one of the three known variants of human GlyT-1, namely GlyT-1a, GlyT-1b or GlyT-1c, or human GlyT-2. The sequences of these GlyT-1 transporters are described in Kim et al., Molec. Pharm. 45: 608-617, 1994, excepting that the sequence encoding the extreme N-terminal of GlyT-1a was merely inferred from the corresponding rat-derived sequence. This N-terminal protein-encoding sequence has now been confirmed to correspond to that inferred by Kim et al. The sequence of the human GlyT-2 is described by Albert et al., U.S. application Ser. No. 08/700,013, filed Aug. 20, 1996, which is incorporated herein by reference in its entirety. Suitable expression vectors include pRc/CMV (Invitrogen), Zap Express Vector (Stratagene Cloning Systems, LaJolla, Calif.; hereinafter xe2x80x9cStratagenexe2x80x9d), pBk/CMV or pBk-RSV vectors (Stratagene), Bluescript II SK +/xe2x88x92 Phagemid Vectors (Stratagene), LacSwitch (Stratagene), pMAM and pMAM neo (Clontech), among others. A suitable expression vector is capable of fostering expression of the included GlyT DNA in a suitable host cell, preferably a non-mammalian host cell, which can be eukaryotic, fungal, or prokaryotic. Such preferred host cells include amphibian, avian, fungal, insect, and reptilian cells.